KR20200108021A - Method for preparing PARP inhibitors and intermediates thereof - Google Patents

Abstract

Methods of making poly ADP ribose polymerase (PARP) inhibitors and intermediates thereof are disclosed herein. This method has a high yield, good product purity, and is more advantageous for industrial production.

Description

Method for preparing PARP inhibitors and intermediates thereof

This application claims priority to CN201810019736.1 (filing date: January 9, 2018) and CN201811547590.4 (filing date: December 18, 2018), the contents of which are incorporated herein by reference in their entirety.

The present application relates to the field of pharmacy, and in particular to a method of preparing a PARP inhibitor and intermediates thereof.

Recently, cancer mortality rates in China have risen markedly. People's lives and quality of life have been seriously threatened by cancer. For the proliferation of malignant tumors, chemotherapy or radiation therapy with conventional chemotherapy drugs has high toxicity and low specificity. Therefore, developing anticancer drugs with high efficacy and low toxicity in today's life sciences is a challenging and important project. Scientific research shows that tumor cells have specific DNA repair mechanisms, which respond quickly and repair damage to chromosomes associated with proliferation control, avoiding the cytotoxic effects of some therapeutic drugs and maintaining survival. The cytotoxic effect of DNA damaging agents can be ameliorated by tumor cell specificity by modulating the repair mechanisms for DNA damage. PARP (poly(ADP-ribose) polymerase), characterized by polyadenosine di phosphate-ribosylating activity, constitutes a superfamily of 18 nuclear and cytoplasmic enzymes. These polypolyadenosine diphosphate-ribosylation effects can modulate the activity of targeted proteins and interactions between proteins, and can regulate many fundamental biological processes including DNA repair and cell death. In addition, it is also associated with genomic stability (see D'Amours et al. Biochem. J, 1999, 342, 249). Because the DNA damage repair mechanism is a major mechanism by which tumor cells develop resistance to chemotherapy drugs and ionizing radiation therapy, PARP is considered an effective target to explore new cancer treatments.

Currently, a series of PARP inhibitors have been disclosed. Among them, CN102686591A discloses an effective PARP inhibitor of formula (I) and a method for its preparation. These compounds have significant advantages in drug efficacy.

[Formula I]

In the method for preparing the compound of formula I, the following compound of formula II was used as the main intermediate, and the yield and purity of the intermediate directly affected the purity and purification problems of the final product.

[Formula II]

Existing manufacturing methods for these intermediates have several drawbacks. WO2004032836 discloses a method for preparing a compound of formula II. In some methods, column chromatography is used for low-efficiency work-up, and the obtained compound of formula II continues to have some impurities, which are difficult to remove and are introduced into the reaction of the final product to affect the purity of the final product. I can. In some methods, purification is carried out by protecting the imino group with BOC followed by deprotection, but this method has many reaction steps and low yield. In addition, the method has a low reaction yield, time-consuming work-up and high cost when used in industrial production, and also the palladium catalyst used in the hydrogenation reaction is not completely removed, which further affects the purity of the product. Thus, there is an urgent need for a process for the industrial production of compounds of formula II with high yield, good product purity and simple work-up.

In order to overcome the shortcomings present in the prior art, the object of the present application is to provide a new method for preparing PARP inhibitors and intermediates thereof.

The present application provides a method for preparing a compound of Formula II':

[Formula II]

[Formula II']

In the above formula,

R ₁ is hydrogen, alkyl, halogen, hydroxy, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyl, -C(O)OR ₂ , -OC(O)R ₂ , -O( CH ₂ ) _n C(O)OR ₂ , -(CH ₂ ) _n NR ₃ R ₄ , -C(O)R ₂ , -NHC(O)R ₂ , -NR ₃ R ₄ , -OC(O)NR ₃ R ₄ or -C(O)NR ₃ R ₄ , wherein each of alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl and benzyl is alkyl, halogen, hydroxy, alkoxy, cycloalkyl, hetero Cycyl, aryl, heteroaryl, oxo, -C(O)OR ₂ , -OC(O)R ₂ , -O(CH ₂ ) _n C(O)OR ₂ , -C(O)R ₂ , -NHC (O)R ₂ , -N ₃ R ₄ , -OC(O)NR ₃ R ₄ or -C(O)NR ₃ R ₄ are optionally substituted independently with one or more substituents;

R ₂ is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is alkyl, halogen, hydroxy, alkoxy, cycloalkyl, Optionally substituted independently with one or more substituents selected from heterocyclyl, aryl, heteroaryl, carboxy or carboxylate ester groups;

Each of R ₃ and R ₄ is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is alkyl, halogen, hydroxy , Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate ester groups are independently optionally substituted with one or more substituents selected from, or

R ₃ and R ₄ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl contains at least one hetero atom selected from N, O or S(O) _m , and the heterocyclyl is alkyl , Halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate ester groups optionally substituted with one or more substituents;

m is selected from 0, 1 or 2;

n is selected from 0, 1 or 2;

X is an acid that may be an inorganic acid or an organic acid (wherein the inorganic acid may be hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, trifluoroacetic acid, etc., and the organic acid is formic acid, acetic acid, sulfonic acid, optionally substituted alkylsulfonic acid , Succinic acid, maleic acid, tartaric acid, citric acid, lactic acid, oxalic acid, gluconic acid, fumaric acid, malonic acid, malic acid, etc.), preferably hydrochloric acid, phosphoric acid and maleic acid, more preferably hydrochloric acid. .

The method comprises reacting a compound of formula II with a corresponding acid.

In some embodiments, R ₁ is -CF ₃ .

The solvent used in the step of reacting the compound of formula II with the corresponding acid is a conventional solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate. , Dioxane, toluene, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol and at least one solvent selected from water, preferably tetrahydrofuran , Ethyl acetate, dioxane, toluene, dimethyl sulfoxide, diethyl ether, isopropyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, and isopropanol.

The molar ratio of the compound of formula II to the corresponding acid can be from 1:1 to 1:10.

In some embodiments, a compound of Formula II′ can be isolated. The isolation method may be a conventional method, such as filtration, solvent removal, and the like. Before or after isolation of the compound of formula II', purification, such as recrystallization, slurriing, column chromatography, and the like can be optionally carried out.

In some embodiments, the method comprises performing a hydrogenation reduction reaction of a compound of formula III to obtain a compound of formula II:

[Formula III]

[Formula II]

.

.

The solvent used in the step of carrying out the hydrogenation reduction reaction of the compound of formula III to obtain the compound of formula II is a conventional solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, At least one solvent selected from tetrahydrofuran, ethyl acetate, dioxane, toluene, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol and water, Preferably it may be one or more solvents selected from methanol, ethanol and isopropanol.

The hydrogenation reduction reaction is preferably carried out in the presence of a catalyst; The catalyst may be a palladium-containing catalyst, such as palladium on carbon.

In addition, the present application provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising the steps of a method for preparing a compound of formula II' as described herein:

[Formula I]

.

.

In some embodiments, the method comprises reacting a compound of Formula II' with a compound of Formula IV:

In the above formula,

R _a is selected from hydroxy, halogen or alkoxy.

In addition, the present application provides a method for purifying a compound of Formula II, wherein the method comprises the steps of reacting a compound of Formula II with a corresponding acid to obtain a compound of Formula II', isolating the compound of Formula II', and And converting the compound of Formula II' to a compound of Formula II.

In some embodiments, R ₁ is -CF ₃ .

The solvent used in the reaction is a conventional solvent such as dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dioxane, toluene, diethyl ether, iso At least one solvent selected from propyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol and water, preferably tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethyl It may be one or more solvents selected from sulfoxide, diethyl ether, isopropyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol and isopropanol.

The molar ratio of the compound of formula II to the corresponding acid can be from 1:1 to 1:10.

The isolation method may be a conventional method, such as filtration, solvent removal, and the like. Before or after isolation of the compound of formula II', purification, such as recrystallization, slurriing, column chromatography, and the like can be optionally carried out.

The conversion method may be a conventional method, for example, a reaction of a compound of formula II' with a base, and the base may be an inorganic or organic base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, and the like.

In some embodiments, the compound of formula II is obtained from a hydrogenation reduction reaction of a compound of formula III.

Further, the present application provides a method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising the steps of a method for purifying a compound of formula II as described herein.

In some embodiments, the method comprises reacting a compound of formula II with a compound of formula IV, wherein R _a is selected from hydroxy, halogen or alkoxy.

In the method for preparing the intermediate of the PARP inhibitor of the present application, it is unexpected that by using the salt-forming purification method, the reaction yield and purity are greatly improved, the product processing time in the production process is shortened, and the production efficiency is greatly increased. . After formation of the salt, the intermediate is in solid form and has a suitable solubility, so that it can be purified by conventional methods, such as recrystallization and slurriing, to improve its purity and effectively prevent impurities originating from the reaction from being introduced into the final product Therefore, this method has an advantage in the reaction and purification of the final product.

Unless stated to the contrary, terms used in this application and in the claims have the meanings set forth below.

The term “alkyl” refers to an aliphatic hydrocarbon group that is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl 2, 2-dimethylpropyl 1-ethylpropyl 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl 1,1,2-trimethylpropyl 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethyl Hexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl , n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl , And various branched isomers thereof. Alkyl is more preferably lower alkyl containing 1 to 6 carbon atoms, non-limiting examples being methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n -Pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl 2,2-dimethylpropyl 1-ethylpropyl 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl 1,1,2-trimethylpropyl 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl may be unsubstituted or substituted, and if alkyl is substituted, the substituent may be substituted at any available linking site, and the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino , Halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy and carboxylate ester groups Is one or more groups independently selected from

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Refers to. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. . Polycyclic cycloalkyl includes cycloalkyl including spiro rings, fused rings or bridged rings.

The term “heterocyclyl” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group containing 3 to 20 ring atoms, wherein at least one ring atom is N, O and S(O) _m , wherein m is an integer of 0 to 2), but -OO-, -OS- or -SS- are excluded from the ring, and the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl contains 3 to 12 ring atoms, wherein 1 to 4 atoms are hetero atoms; More preferably, the heterocyclyl contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, Piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably piperidinyl or pyrrolidinyl. Polycyclic heterocyclyls include heterocyclyls including spiro rings, fused rings or bridged rings.

The term “aryl” refers to a 6-14 membered all-carbon monocyclic ring or fused polycyclic ring (ie, the rings share adjacent pairs of carbon atoms) with a conjugated pi-electron system, preferably 6 To 10-membered aryl, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl ring, a heterocyclyl ring or a cycloalkyl ring, but the ring linked to the parent structure is an aryl ring, and non-limiting examples of aryl include:

.

.

Aryl may be unsubstituted or substituted, and when substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl , At least one group independently selected from heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy and carboxylate ester groups, preferably phenyl.

The term “heteroaryl” refers to a 5 to 14 membered heteroaromatic system comprising 1 to 4 heteroatoms selected from O, S and N. Heteroaryl is preferably 5 to 12 membered heteroaryl, for example imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadia Zolyl, pyrazinyl, and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; More preferably, they are pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl ring, heterocyclyl ring or cycloalkyl ring, but the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples of heteroaryl include:

.

.

Heteroaryl may be optionally unsubstituted or substituted, and when substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy and carboxylate ester groups.

The term “alkoxy” refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally unsubstituted or substituted, and when substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, At least one group independently selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy and carboxylate ester groups.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to the group -OH.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "benzyl" refers to -CH ₂ -phenyl.

The term "oxo" refers to =O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate ester" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl).

“Arbitrary” or “arbitrarily” does not require, but may occur, the events and circumstances described subsequently, and such description includes situations in which an event or context has occurred or has not occurred. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl does not need to be present, but may be present, and this technique is a situation where heterocyclyl is substituted with alkyl and heterocyclyl is not substituted with alkyl. Include situations that are not.

"은 배열을 명시하지 않고, 즉, 구성적 이성질체가 화학 구조에서 존재하는 경우, 결합 "

"은 "

" 또는 "

"일 수 있거나, 이는 "

" 및 "

" 배열 모두를 함유할 수 있다.In the chemical structure of the compounds herein, the bond"

"A bond does not specify an arrangement, ie, when a constitutive isomer is present in the chemical structure"

"Is"

" or "

"May be, or this is "

"And"

"Can contain all of the arrangements.

Hereinafter, the present application is described in detail in conjunction with specific embodiments so that those skilled in the art may more fully understand the present application. Certain embodiments are merely for describing the technical solutions of the present application, and the present application is not limited thereto.

Embodiment 1:

Compound 1 (5.0 kg), 10% palladium on carbon (250 g) and methanol (80 L) were added to the reactor, and the hydrogenation reaction was carried out at 25° C. for 24 hours under 0.4 MPa. Palladium on carbon was removed by filtration and the filter cake was washed with methanol. After the filtrate was collected and evaporated to dryness under reduced pressure, ethyl acetate (20 L) was added to the resulting concentrate. After the solid was dissolved by stirring, the mixture was cooled to 0° C. in an ice-water bath, adjusted to pH 2-3 with 4 M hydrogen chloride in ethyl acetate, stirred and filtered. The filter cake was slurried with ethyl acetate (20 L) at room temperature for 3-4 hours. The mixture was filtered and the filter cake was dried under vacuum at 45° C. for 6 to 8 hours to give compound 3 (5.5 kg) as a solid in a yield of 91.7% and an HPLC purity of 99.69%.

Embodiment 2:

According to embodiment 19 of CN102686591A, the obtained compound 3 (2 g) and compound 4 (2.79 g) were reacted to give a compound of formula I (3.6 g) in a yield of 87.8%.

Embodiment 3:

At room temperature, after dissolving compound 2 (prepared according to the method disclosed in WO2009025784) (2.0 g) in isopropanol (30 mL), the pH was adjusted to 3 by adding concentrated sulfuric acid while stirring. The resulting mixture was stirred at room temperature and no solid precipitated. Then, the mixture was poured into n-hexane (150 mL) and further stirred at room temperature. No solid precipitated and the compound 2 sulfate salt in solid form was not obtained.

Embodiment 4:

At room temperature, after dissolving compound 2 (1.11 g) in isopropanol (10 mL), a 15% phosphoric acid/isopropanol solution was added dropwise while stirring to adjust the pH to 3. The resulting mixture was stirred at room temperature and filtered. The filter cake was washed with isopropanol and dried under vacuum to give compound 2 phosphate salt (1.46 g) in solid form with a purity of 87.1% and an HPLC purity of 99.72%.

Embodiment 5:

At room temperature, after dissolving compound 2 (1.28 g) in isopropanol (10 mL), a 20% acetic acid/isopropanol solution was added dropwise while stirring to adjust the pH to 3. The resulting mixture was stirred at room temperature and no solid precipitated. The mixture was poured into n-hexane (100 mL) and further stirred at room temperature. No solid precipitated and the compound 2 acetate salt in solid form was not obtained.

Embodiment 6:

At room temperature, after dissolving compound 2 (1.05 g) in isopropanol (10 mL), a 15% citric acid/isopropanol solution was adjusted to pH 3 while stirring. The resulting mixture was stirred at room temperature and no solid precipitated. The mixture was poured into n-hexane (100 mL) and further stirred at room temperature. No solid precipitated and the compound 2 citrate salt in solid form was not obtained.

Embodiment 7:

At room temperature, after dissolving compound 2 (1.12 g) in isopropanol (10 mL), maleic acid (0.74 g) was added while stirring. The resulting mixture was stirred at room temperature and filtered. The filter cake was washed with isopropanol and dried under vacuum to give compound 2 maleate salt (1.51 g) in solid form in a yield of 84.6%.

As this application has been described in accordance with certain embodiments thereof, certain modifications and equivalent modifications will be apparent to those skilled in the art, and are included within the scope of the present invention.

Claims (15)

A method for preparing a compound of Formula II', wherein the method comprises reacting a compound of Formula II with a corresponding acid:
[Formula II]

[Formula II']

In the above formula,
R ₁ is hydrogen, alkyl, halogen, hydroxy, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyl, -C(O)OR ₂ , -OC(O)R ₂ , -O( CH ₂ ) _n C(O)OR ₂ , -(CH ₂ ) _n NR ₃ R ₄ , -C(O)R ₂ , -NHC(O)R ₂ , -NR ₃ R ₄ , -OC(O)NR ₃ R ₄ or -C(O)NR ₃ R ₄ , wherein each of alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl and benzyl is alkyl, halogen, hydroxy, alkoxy, cycloalkyl, hetero Cycyl, aryl, heteroaryl, oxo, -C(O)OR ₂ , -OC(O)R ₂ , -O(CH ₂ ) _n C(O)OR ₂ , -C(O)R ₂ , -NHC (O)R ₂ , -N ₃ R ₄ , -OC(O)NR ₃ R ₄ or -C(O)NR ₃ R ₄ are optionally substituted independently with one or more substituents;
R ₂ is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is alkyl, halogen, hydroxy, alkoxy, cycloalkyl, Optionally substituted independently with one or more substituents selected from heterocyclyl, aryl, heteroaryl, carboxy or carboxylate ester groups;
Each of R ₃ and R ₄ is independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is alkyl, halogen, hydroxy , Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate ester groups are independently optionally substituted with one or more substituents selected from, or
R ₃ and R ₄ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein the heterocyclyl contains at least one hetero atom selected from N, O or S(O) _m , and the heterocyclyl is alkyl , Halogen, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate ester groups optionally substituted with one or more substituents;
m is selected from 0, 1 or 2;
n is selected from 0, 1 or 2;
X is an inorganic acid and an organic acid, preferably hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, trifluoroacetic acid, formic acid, acetic acid, sulfonic acid, optionally substituted alkylsulfonic acid, succinic acid, maleic acid, tartaric acid, citric acid, lactic acid , Oxalic acid, gluconic acid, fumaric acid, malonic acid and malic acid, more preferably hydrochloric acid, phosphoric acid and maleic acid, most preferably hydrochloric acid. The method of claim 1,
R ₁ is -CF ₃ , the production method. The method of claim 1,
The solvent used in the step of reacting the compound of formula II with the corresponding acid is dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dioxane, toluene, diethyl ether , Isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol and at least one solvent selected from water, preferably tetrahydrofuran, ethyl acetate, dioxane, toluene, Dimethyl sulfoxide, diethyl ether, isopropyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol and at least one solvent selected from isopropanol. The method of claim 1,
The preparation method, wherein the molar ratio of the compound of formula II to the corresponding acid is 1:1 to 1:10. The method of claim 1,
A method of preparation comprising isolating a compound of Formula II′. The method of claim 1,
A preparation method comprising the step of performing a hydrogenation reduction reaction of a compound of formula III to obtain a compound of formula II:
[Formula III]

[Formula II]

. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising preparing a compound of formula (II') according to the method defined in any one of claims 1 to 6, Manufacturing method:
[Formula I]

. The method of claim 7,
A preparation method comprising the step of reacting a compound of formula II' with a compound of formula IV:

In the above formula,
R _a is selected from hydroxy, halogen or alkoxy. A method for purifying a compound of Formula II, wherein the method performs a reaction of a compound of Formula II and a corresponding acid to obtain a compound of Formula II', isolating the compound of Formula II', and A purification method comprising the step of converting a compound of formula II' to a compound of formula II:
[Formula II]

[Formula II']

In the above formula,
R ₁ and X are as defined in claim 1. The method of claim 9,
R ₁ is -CF ₃ , the method of purification. The method of claim 9,
The solvent used in the reaction is dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dioxane, toluene, diethyl ether, isopropyl ether, methyl tert-butyl ether , Dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol and at least one solvent selected from water, preferably tetrahydrofuran, ethyl acetate, dioxane, toluene, dimethyl sulfoxide, diethyl ether, iso Propyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol and at least one solvent selected from isopropanol. The method of claim 9,
The method of purification, wherein the molar ratio of the compound of formula II to the corresponding acid is 1:1 to 1:10. The method of claim 9,
Purification method comprising the step of carrying out a hydrogenation reduction reaction of the compound of formula III to obtain a compound of formula II:
[Formula III]

[Formula II]

. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising purifying the compound of formula II according to the method defined in any one of claims 9 to 13 Way:
[Formula I]

. The method of claim 14,
A preparation method comprising the step of reacting a compound of formula II with a compound of formula IV:
[Formula IV]

In the above formula,
R _a is selected from hydroxy, halogen or alkoxy.